System and method of administering a pharmaceutical gas to a patient

ABSTRACT

Described are methods and systems for delivering pharmaceutical gas to a patient. The methods and systems utilize a high flow valve and a low flow valve in parallel flow paths. The pharmaceutical gas may be provided as a pulse during the first half of the patient&#39;s inspiratory cycle.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. §120 of U.S. patentapplication Ser. No. 13/287,663, filed Nov. 2, 2011 and U.S. patentapplication Ser. No. 13/284,433, filed Oct. 28, 2011, which arecontinuations of U.S. patent application Ser. No. 12/430,220, filed Apr.27, 2009, now U.S. Pat. No. 8,091,549, issued Jan. 10, 2012, which is acontinuation of U.S. patent application Ser. No. 11/231,554, filed Sep.21, 2005, now U.S. Pat. No. 7,523,752, issued Apr. 28, 2009, the entiredisclosures of which are hereby incorporated by reference herein

BACKGROUND

The present invention relates to methods and systems for administering apharmaceutical gas to a patient and, more particularly, to methods andsystems for introducing carbon monoxide CO or nitric oxide NO to apatient.

The normal or conventional way of giving a pharmaceutical drug to apatient is to prescribe the dose based on the quantity of drug (usuallyin weight) per unit weight of the patient (e.g. mg/Kg) with the dosebeing specified to be delivered over a period of time or being repeatedat specified intervals of time. This allows the user to control thequantity of drug and ensures the quantity of drug being delivered is inproportion to the patient's size. This is to reduce the patient topatient variability in response to the drug due to the size of thepatient i.e. a 7 Kg baby will not get the same quantity of drug as a 80Kg adult.

In recent times there have been a number of gases which have been shownto have pharmaceutical action in humans and animals. Examples includeNitric Oxide (NO) Zapol et al U.S. Pat. No. 5,485,827 and more recentlyCarbon Monoxide (CO) Otterbein et al (U.S. Published Patent ApplicationNo. 2003/0219496). In the Otterbein patent application, CO is describedas having a pharmacological action in a number of medical conditionsincluding ileus and vascular disease.

In these cases, the carbon monoxide gas needs to be delivered to thepatients alveoli where it can move across the alveolar membrane and intothe blood stream where its action can take effect. The current dosingused in these cases is for the patient to breath at a specifiedconcentration of CO in ppm for a specified period of time. Accuratedosing of CO for these treatments is important as CO reacts with thehemoglobin in the blood to form carboxyhemoglobin which means thehemoglobin is no longer able to carry oxygen to the tissues of the body.If too much CO is given, the patient may exhibit the toxic effects of COfor which it is usually known.

There is a tight window for CO delivery between the therapeutic leveland the level that causes carboxyhemoglobin above safe levels. Up untilnow CO has been delivered as a constant concentration in the gasbreathed by the patient/animal for a specified period of time. Forexample in reference 3 of the Otterbein publication, (Example 2 pg 13)the therapeutic dose delivered to mice for the treatment of ileus was250 ppm of CO for 1 hour.

However, this method of dosing CO can be associated with largevariability in the actual dose being delivered to the animal/humansalveoli. This variability is because the quantity of CO being deliveredto the animal/patient is dependent on a number of variables including,but not limited to, the patients tidal volume, respiratory rate,diffusion rate across the alveolar and ventilation/perfusion (V/Q)matching.

The amount of CO delivered into a patient's alveoli can be determined bythe ideal gas law as shown in the following equation:N=PV/(R _(u) T)  (1)Where: N is the number of moles of the gas (mole) P is the absolutepressure of the gas (joule/m³) V is the volume of the particular gas(m³), R_(u) is the universal gas constant, 8.315 joule/mole-K and T isthe absolute temperature (K).

If we assume atmospheric pressure (101,315 joule/m³) and 20° C. (293 K)as the temperature and we express the volume in mL (10⁻⁶ m³), thenequation (1) reduces to:N=4.16×10⁻⁵V (moles)  (2)

Equation (2) can be used to calculate the number of moles of gasdelivered to a patient's alveolar volume over a period of time whengiven a specified concentration by using the following equation:N _(CO) =RR·t·C _(CO)·10⁻⁶·4.16×10⁻⁵V_(a)  (3)Where; C_(CO) is the concentration of CO (ppm), V_(a) is the alveolarvolume (mL), RR is the respiratory rate (BPM) and t is the time inminutes.

For example, if the CO dose for ileus in humans was 250 ppm of CO forone hour (60 minutes), the alveolar volume is 300 mL and the patientsrespiratory rate is 12 breaths per minute (bpm) then the amount of COgas in moles delivered to the patients alveoli over that period wouldbe:N _(CO)=12·60·250·10⁻⁶·4.16×10⁻⁵·300=2.25×10⁻³ moles

This can be converted into the mass of drug delivered (M_(CO)) using thegram molecular weight of CO which is 28 as shown in the followingequation:M _(CO) =N _(CO)·28=63×10⁻³ g=63 mg  (4)

However, although this works for a given set of assumptions, aspontaneous patient's respiratory rate can vary widely from perhaps 8 to20 breaths per minute depending on circumstances and the patient'salveolar volume per breath can also vary significantly from say 200 to400 mL depending on the metabolic need. These variables can have adramatic effect on the amount of gaseous drug being delivered to thepatient over the same period of time. For instance, if the patientsrespiratory rate was 8 bpm and the alveolar volume was 200 mL, the COdose delivered to the patients alveoli would have been 27.8 (mg).Likewise if the patients respiratory rate was 20 bpm and the alveolarvolume was 400 mL, then the dose delivered to the patients alveoli wouldhave been 139.2 (mg) thus representing a five-fold difference in theamount of drug being delivered.

This means, in the example of CO, the quantity of gaseous drug a patientgets as measured in grams could vary substantially depending on thepatient's ventilation pattern. For a dose based on constantconcentration and time, the effect of these variables could mean that anindividual patient could get significantly higher or lower doses of COin grams and this could result in either high unsafe levels ofcarboxyhemoglobin or doses too low to be effective. Although not all thegaseous drug delivered to the alveoli will be taken up by the body'sbloodstream (due to variables such as cardiac output and the diffusioncoefficient of the gas) controlling the amount delivered to the alveolitakes away a major source of variability.

In addition, there is a need to administer NO to a patient in apredetermined quantity as described in “Cell-free hemoglobin limitsnitric oxide bioavailabllity in sickle-cell disease”, Nature Medicine,Volume 8, Number 12, December 2002, pages 1383 et seq. This paperdescribes the use of inhaled NO to react with cell free hemoglobin toform plasma methemoglobin and so reduce the ability of the cell freehemoglobin in the plasma to consume endogenously produced NO (FIG. 5,page 1386). The quantity of NO delivered to the patient blood needs tobe equivalent to the amount of cell free hemoglobin that is in thepatients plasma. The amount of NO delivered to a sample of sickle cellpatients was 80 ppm of NO for 1.5 hours. However, there was variabilityin the amount of methemoglobin produced in individual patients as shownby the error bars on FIG. 4 b. So, in a similar way to the CO example, aknown quantity of NO needs to be delivered to a patient to provide thedesired therapeutic effect and again it is important to remove anyvariability of delivery because of differences in the individualpatient's respiratory pattern.

Accordingly, it would be advantageous to have a system and method ofintroducing pharmaceutical gases (such as carbon monoxide and nitricoxide) that allows for the precise control of a known quantity of thepharmaceutical gas to be delivered to the patients alveoli and which isnot subject to change based on the patients respiratory patterns.

SUMMARY

Accordingly, the present invention relates to a system and method foradministering a pharmaceutical gas, such as nitric oxide, to thepatient. One aspect of the present invention relates to a nitric oxidedelivery system comprising an inlet to connect to a source ofpharmaceutical gas comprising nitric oxide, an outlet to connect to adevice that introduces the pharmaceutical gas to the patient, a low flowvalve in fluid communication with the inlet and outlet, a high flowvalve in fluid communication with the inlet and outlet and in parallelto the low flow valve, and a gas control system that delivers a pulse ofthe pharmaceutical gas through one or more of the low flow valve and thehigh flow valve. The low flow valve delivers the pharmaceutical gas at afirst flow rate and the high flow valve delivers the pharmaceutical gasat a second flow rate that is higher than the first flow rate. Accordingto one or more embodiments, the flow rate of the low flow valve is about1 L/min and/or the flow rate of the high flow valve is about 6 L/min. Insome embodiments, the ratio of the high flow rate to the low flow ratemay be about 6:1.

In one or more embodiments, the gas control system delivers the pulse ofpharmaceutical gas during the first half of the patient's inspiratorycycle. The nitric oxide delivery system may further comprise a patienttrigger sensor that senses the beginning of a patient's inspiratorycycle.

The device that introduces the pharmaceutical gas to the patient may bein fluid communication with a ventilator. In some embodiments, thedevice that introduces the pharmaceutical gas to the patient maycomprise one or more of a nasal cannula, an endotracheal tube and a facemask.

The source of pharmaceutical gas may comprise nitric oxide in a knownconcentration in a carrier gas. In one or more embodiments, the gascontrol system controls the volume of pharmaceutical gas deliveredduring the patient's breath based upon the concentration of the nitricoxide in the carrier gas.

In some embodiments, a desired quantity of the pharmaceutical gas isadministered to the patient irrespective of the patient's respiratorypatterns.

Another aspect of the present invention pertains to a method ofadministering a pharmaceutical gas comprising nitric oxide to a patient.In embodiments of this aspect, the method comprises providing a nitricoxide delivery system having a low flow valve and a high flow valve inparallel flow paths, sensing the beginning of patient inspiration anddelivering a pulse of pharmaceutical gas comprising nitric oxide to thepatient during inspiration through one or more of the low flow valve andthe high flow valve. The method may further comprise determining thepatient's respiratory rate.

According to one or more embodiments of this aspect, the flow rate ofthe low flow valve is about 1 L/min and/or the flow rate of the highflow valve is about 6 L/min. In some embodiments, the ratio of the highflow rate to the low flow rate may be about 6:1.

In one or more embodiments, the pulse of pharmaceutical gas is deliveredduring the first half of the patient's inspiratory cycle.

The source of pharmaceutical gas may comprise nitric oxide in a knownconcentration in a carrier gas. In one or more embodiments, the gascontrol system controls the volume of pharmaceutical gas deliveredduring the patient's breath based upon the concentration of the nitricoxide in the carrier gas.

In some embodiments, a desired quantity of the pharmaceutical gas isadministered to the patient irrespective of the patient's respiratorypatterns.

These and other features and advantages of the present invention willbecome more readily apparent during the following detailed descriptiontaken in conjunction with the drawings herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are views of a front panel of an apparatus for carryingout the present invention showing different user options;

FIG. 3 is a schematic view of the present invention used with aspontaneously breathing patient; and

FIG. 4 is a schematic view of the present invention used with a patientbeing breathed by means of a ventilator.

DETAILED DESCRIPTION

In the following detailed description, CO is used as the pharmaceuticalgas but the description can also be valid for NO. Referring now to FIG.1, there is shown a front view of an apparatus that can be used incarrying out the present invention. As can be seen, there is a frontpanel 10 that can be a part of the apparatus and on that panel there areinput setting knobs and displays which allow the user to set and monitorthe amount of CO that is to be delivered to the patient.

The means for determining the desired quantity of CO to be delivered isby means of a setting control including an input setting knob 12 withthe set amount being shown on the setting display 8. The units shown inFIG. 1 are in milligrams per kilogram that is, the units are measured ina dosage per kilogram of the patient's ideal body weight. Along withthat input, there is a further input 14 whereby the user can enter thepatient's ideal body weight in kilograms with the amount also displayedon the setting display 8. With those inputs, the user can set thequantity of the pharmaceutical gas to be administered to the patient inproportion to the size of the patient and which reduces the patient topatient variability in response to the pharmaceutical gas due to thesize of the patient, i.e. a 7 kilogram baby will not be administered thesame quantity of the pharmaceutical gas as a 80 kilogram adult.

The front panel 10 also has a monitor display 6 which can display totaldose of CO (mg) to be delivered (shown at 16) as calculated formultiplying the dosage/kg by the patients ideal body weight in kg.

Once the desired quantity of gaseous drug has been set on the device thesystem then determines the amount of pharmaceutical gas that is to bedelivered in each breath and the amount of time and/or the number ofbreaths that it will take to deliver the total desired quantity of drug.The monitor display 6 can also display a running total of the delivereddose of CO (mg) (shown at 17) as it is delivered to the patient so theuser can monitor the progress of the treatment. This can be updated eachbreath as more pharmaceutical gas is delivered.

As stated, the units illustrated in FIG. 1 are in metric units, however,it can be seen that other units of mass and volume could be used incarrying out the present invention i.e. ounces and cubic inches andother designs of a front panel can be used as will later be understood.

Referring to FIG. 2, there is shown a similar front panel 10 for theapparatus as shown in FIG. 1 but illustrating a different user settingoption. The desired quantity of CO to be delivered to the patient isprescribed as a rate of delivery by means of a setting control includingan input setting knob 13 and is in units of mg/hr of CO to be delivered.In this option, the device also allows the time duration (in hours) oftreatment to be set by a means of an input setting knob 15. If required,the input setting by input setting knob 15 could be set to continuouswhere the dose per hour would run continuously until the user changedthe setting. With these input settings, the apparatus can calculate anddisplay the desired quantity of the pharmaceutical gas to beadministered to the patient.

Also, as in FIG. 1, the front panel 10 also has a monitor display 6which can display total dose of CO (mg) to be delivered (shown at 16) ascalculated by multiplying the dosage/hr by the total time duration(hr.). Once the desired quantity of pharmaceutical gas has been set onthe device, the system then determines the amount of pharmaceutical gasto be delivered in each breath and the amount of time and/or the numberof breaths that it will take to deliver the total desired quantity ofdrug. As before, the monitor display 6 can display a running total ofthe delivered dose of CO (mg) (shown at 17) as it is delivered to thepatient so the user can monitor the progress of the treatment. This canbe updated each breath as more pharmaceutical gas is delivered.

As can be appreciated, FIGS. 1 and 2 illustrate two of the many optionsfor setting the desired quantity and duration of pharmaceutical gastherapy. These options are not meant to be exhaustive and there areother setting options described or that can be understood from thedetailed descriptions that follow.

Once the desired quantity of gaseous drug has been set on the device,the gas control system can then determine the amount of pharmaceuticalgas to be delivered in each breath and the amount of time and/or thenumber of breaths that it will take to deliver the desired quantity ofpharmaceutical gas.

There are a number of different approaches that the gas control systemcan use to determine the amount per breath and how long to deliver thatdose so the desired quantity of pharmaceutical gas is deliveredindependent of the respiratory pattern of the patient:

a) The user can set the quantity of pharmaceutical gas to be deliveredduring each breath (M_(CO) breath) and the gas control system calculatesthe number of breaths (n_(breaths)) which will be required to deliverthe total quantity of pharmaceutical gas (M_(CO)) i.e.n _(breaths) =M _(CO) /M _(CO breath)  (5)

Once the total number of breaths (n_(breaths)) required has beendetermined the value can be displayed on the front panel 12 by means ofdisplay 16 to inform the user of the number of breaths.

b) The user can set the number of breaths (n_(breaths)) that willadminister the total quantity of the pharmaceutical gas and the systemcalculates the amount per breath (M_(CO breath)) to be delivered.M _(CO breath) =M _(CO) /n _(breaths) (mg)  (6)

Once the amount per breath (M_(CO breath)) to be delivered has beendetermined, the value can be displayed on the front panel 10 to informthe user of the amount.

(c) The user could set the time duration for which the treatment is tobe delivered over. The amount per breath would then be determined bycalculating the quantity per minute and then, by monitoring the patientsrespiration rate in breaths per minute, the amount of breath can becalculated. This calculation can be repeated after every breath so anychanges in the patients respiratory rate does not affect the overallquantity of gaseous drug being delivered.

d) If the desired quantity of pharmaceutical gas was entered as a doseper Kg of the patient's ideal body weight (μg/kg) along with thepatient's ideal body weight (Kg) then the amount per breath(M_(CO breath)) can be determined as a function of the patient's idealbody weight (IBW), the set dose per kilogram (M_(kg)) and the patient'smonitored respiratory rate (RR) or combinations thereof;

M_(CO) breath=f (IBW, M_sub_kg, RR) and the number of breaths can thenbe calculated as;n _(breaths) =M _(CO) /M _(CO breath)  (7)

Once the amount per breath (M_(CO) breath) and the number of breaths(n_(breaths)) required to be delivered has been determined, the valuescan be displayed on the front panel 10 to inform the user of the amountsthe device has selected.

e) Instead of the ideal body weight (IBW) of the patient, the height andsex of the patient could be entered (which is how IBW is determined).

f) If the desired quantity of pharmaceutical gas per unit of time isentered into the device, then the device can calculate the quantity perbreath to be delivered to the patient based on the current monitoredrespiratory breath rate (as determined by the breath trigger sensor).This quantity per breath can be recalculated after every breath when newinformation on the respiratory rate is available to ensure the quantityper unit of time is maintained even if the patient respiratory breathpattern changes over time.

g) There are also other ways of varying the quantity of pharmaceuticalgas delivered per breath to ensure the quantity per unit of time ismaintained even if the patients respiratory rate changes. Anotherexample is where the device has two different amounts of delivery perbreath, a high amount and a low amount. The device chooses which one touse based on the calculated quantity per unit of time being deliveredover the past number of breaths. If the amount per unit of time isgreater than required, it uses the low amount per breath until thesituation corrects itself; likewise, if the quantity per unit of time isrunning low, then the unit switches to the high amount per breath.

The device can also have programmed limits which restrict the maximumand minimum values that can be selected for M_(CO) breath so that thesystem doesn't select inappropriately too high or too low values. Theselimits can be set to vary based on the patient's ideal body weight, orother indicator of the patient size such as the patient's height, or therespiratory rate of the patient.

The aforesaid information is sufficient for the system of the presentinvention to deliver the dose to the patient and to determine the amountper breath, time of administration or other parameter in order tocommence the administration of CO and to terminate that administrationwhen the user set quantity of the pharmaceutical gas has been deliveredto the patient.

Turning now to FIG. 3, there is shown a schematic of a system that canbe used to carry out the present invention when the patient is breathingspontaneously. As can be seen, there is a patient device 18 thatdelivers the dosage of the pharmaceutical gas from the gas deliverysystem 22 to the patient 41 via a gas conducting conduit 19. Asindicated, the patient device 18 can be any one of a variety of devicesthat actually directs the pharmaceutical gas into the patient and may bea nasal cannula, a mask, an endotracheal tube and the like.

With the FIG. 3 embodiment, there is a source of the pharmaceutical gasby means of a gas supply tank 20 containing the pharmaceutical gasgenerally in a carrier gas. When the pharmaceutical gas is carbonmonoxide, for example, the conventional, commercially available carriergas is air. The supply of carbon monoxide and air is provided inconcentrations of 3000 ppm however, concentrations within the range of1000 to 5000 ppm of CO in air are also possible alternatives. In thecase of NO as the pharmaceutical gas, the carrier gas is conventionallynitrogen and the typical available concentrations range from 100 ppm to1600 ppm.

Accordingly, from the supply tank 20, there is a tank pressure gauge 21and a regulator 23 to bring the tank pressure down to the workingpressure of the gas delivery system 22. The pharmaceutical gas entersthe gas delivery system 22 through an inlet 24 that can provide a readyconnection between that delivery system 22 and the supply tank 20 via aconduit. The gas delivery system 22 has a filter 25 to ensure nocontaminants can interfere with the safe operation of the system and apressure sensor 27 to detect if the supply pressure is adequate andthereafter includes a gas shut off valve 26 as a control of thepharmaceutical gas entering the deliver system 22 and to provide safetycontrol in the event the delivery system 22 is over delivering thepharmaceutical gas to the patient. In the event of such over delivery,the shut off valve 26 can be immediately closed and an alarm 42 soundedto alert the user that the gas delivery system has been disabled. Assuch, the shut off valve 26 can be a solenoid operated valve that isoperated from signals directed from a central processing unit includinga microprocessor.

Downstream from the shut off valve 26 is a flow control system thatcontrols the flow of the pharmaceutical gas to the patient through thepatient device 18. In the embodiment shown, the flow control systemcomprises a high flow control valve 28 and a low control valve 30 andjust downstream from the high and low flow control valves 28, 30,respectively, are a high flow orifice 32 and a low flow orifice 34 andthe purpose and use of the high and low flow valves 28, 30 and the highand low flow orifices 32, 34 will be later explained. A gas flow sensor36 is also located in the flow of pharmaceutical gas to the patientdevice 18 and, as shown, is downstream from the flow control system,however, the gas flow sensor 36 may alternatively be located upstream ofthe flow control system.

Next, there is a patient trigger sensor 38. When the patient breathes induring inspiration it creates a small sub atmospheric pressure in thenose or other area where the patient device 18 is located, and hence inthe patient device 18 itself. The patient trigger sensor 38 detects thispressure drop and provides a signal indicative of the start ofinspiration of the patient. Similarly, when the patient breathes outthere is a positive pressure in the patient device 18 and the patienttrigger sensor 38 detects that positive pressure and provides a signalindicative of the beginning of expiration. This allows the patienttrigger sensor 38 to determine not only the respiratory rate of thepatient but also the inspiratory and expiratory times.

Finally there is a CPU 40 that communicates with the patient triggersensor 38, the high and low flow valves 28, 30, the gas shut off valve26 and other components in order to carry out the purpose and intent ofthe present invention. The CPU 40 may include a processing componentsuch as a microprocessor to carry out all of the solutions to theequations that are used by the gas delivery system 22 to deliver thepredetermined quantity of the pharmaceutical gas to a patient. The CPU40 is connected to the front panel 10 where the user can enter settingsand monitor therapy.

The use of the delivery system 22 of the present invention forspontaneous breathing can now be explained. When the delivery system 22detects by means of the patient trigger sensor 38 that inspiration hasstarted, there is a signal that is provided to the CPU 40 to deliver adose of a pharmaceutical gas (M_(CO) breath) into the patient'sinspiratory gas flow, preferably during the first ½ of the inspiratorycycle. This amount per breath has been determined based on the desiredquantity of pharmaceutical gas that has been set on the system and thecalculations made in a) to g) described earlier.

The actual volume of gas delivered during the breath depends on theconcentration of the pharmaceutical gas in the carrier gas that issupplied by the supply tank 20. A typical source concentration (C_(CO))for CO would be 3000 ppm (range 500 to 5000). The volume of source gas(V_(d)) per breath to provide a dose per breath (M_(CO) breath) when thesource of CO is 3000 ppm is given by the following equation, combiningequations 2, 3, 4 and 6;V _(d) =M _(CO breath)/(28·C _(CO)·4.16×10⁻¹¹)  (8)

Given that M_(CO)=60×10⁻³ (g), C_(CO)=3000 (ppm), n_(breaths)=600, thenV_(d)=28.6 (mL).

To deliver the volume of source gas per breath (V_(d)), that is, thepharmaceutical gas and the carrier gas, the delivery system 22 opens aflow control valve, such as high flow valve 28 or low flow valve 30 toallow the gas to flow to the patient until the volume per breath (V_(d))has been delivered. The presence of the high flow orifice 32 and the lowflow orifice 36 limits the flow of gas to a fixed set level during theperiod that the high or low flow valves 28, 30 are open so the deliverysystem 22 can determine the period of time the high or low flow valves28, 30 should be open to deliver the volume per breath (V_(d)) required.Also, as another option, the flow can be determined by the gas flowsensor 36 to monitor the gas flow to the patient device 18 and thus tothe patient and can shut off the appropriate high or low flow controlvalve 28, 30 when the desired predetermined quantity of pharmaceuticalgas dose has been delivered to the patient.

As can be seen, to provide enough range to cover all the possible doses,the use of multiple flow valves, that is, the high flow valve 28 and thelow flow valve 30 along with corresponding multiple orifices, high floworifice 32 and low flow orifice 34, can be used in parallel so as toprovide high and low ranges of gas flow. For instance, the low flow gasflow through the low flow valve 30 could be set to 1 L/min and the highflow gas flow through the high flow control valve 28 could be set to 6L/min. The flow range of the particular gas flow valve is selected toensure that the volume of gas per breath (V_(d)) can be delivered to thepatient in at least ½ the inspiratory time.

As an example, if the patient was breathing at 12 breaths per minute andhad an I:E ratio of 1:2 then the inspiratory time would be 1.66 secondsand half that would be 0.83 seconds.

The time (t) taken to deliver a V_(d) of 28 mL can be calculated asfollows.t=V _(d)60/(Q·1000)(secs)  (9)

When Q (the flow of gas when the high flow valve 28 is open)=6 L/minst=0.28 (secs).

That time is therefore well within ½ the inspiratory time allowed of0.83 seconds.

The delivery system 22 can also include monitoring and alarm features toalert the user if the delivery system 22 is not working correctly. Thosealarm conditions can be determined by the CPU 40 and the alarm 42activated to alert the user to the particular fault condition. The alarm42 can be audible, visual or both and the alarm conditions can be anyone or all of the following: No breath detected Low source gas pressureInaccurate delivery of the volume per breath (V_(d)) Over delivery ofthe volume per breath (V_(d)) Under delivery of the volume per breath(V_(d))

Under certain conditions, such as when the delivery system 22 is overdelivering the pharmaceutical gas, the CPU 40 may signal the gas shutoff valve 26 and immediately cease any further delivery of thepharmaceutical gas and the alarm 42 also activated.

The use of the alarm 42 can also be an alternative to actually shuttingoff the supply of the pharmaceutical gas to a patient when thepredetermined desired quantity of pharmaceutical gas has been fullydelivered to the patient. In such case, as an alternative to ceasing thefurther supply of the pharmaceutical gas to the patient, the deliverysystem 22 may, by means of the CPU 40, activate the alarm 42 to alertthe user that the total predetermined desired quantity of thepharmaceutical gas has been delivered. The user can then determinewhether to manually deactivate the delivery system 22 or continue thedelivery of the pharmaceutical gas under more watchful control of thepatient's status.

Turning now to FIG. 4, there is shown a schematic view of a gas deliverysystem 44 used in conjunction with a patient being breathed by aventilator 46. In the FIG. 4 embodiment, again there is a supply tank 20that includes a conventional gas regulator 23 and pressure gauge 21 tosupply the pharmaceutical gas along with the carrier gas to an inlet 24in the gas delivery system 44. Briefly summarizing the components of theFIG. 4 embodiment, since they are basically the same components asdescribed with respect to the FIG. 3 embodiment, there can be a filter25 and a pressure sensor 27 in the gas delivery system 44. Again thereis a shut off valve 26 to control the overall flow of the pharmaceuticalgas through the gas delivery system 44.

The high and low flow control valves 28 and 30 control the flow of thepharmaceutical gas through the gas delivery system 44 and, the high andlow flow valves 28, 30 operate as described with respect to the FIG. 3embodiment with high and low flow orifices 32, 34 located downstream ofthe flow control valves.

Again there is a gas flow sensor 36 and a patient trigger sensor 66,both of which communicate with the CPU 40. With this embodiment,however, the pharmaceutical gas is carried through an outlet conduit 70to a patient device 72 that also receives the breathing gas from theventilator 46. As such, the ventilator 46 delivers a flow of gas throughthe inspiratory limb 74 and gas is returned to the ventilator 46 throughthe expiratory limb 76.

The flow of gas from the ventilator 46 is thus supplemented by the flowof pharmaceutical gas from the gas delivery system 44 where that gas ismixed at or proximate to the patient device 72 for introduction into thepatient 78. Since all of the pharmaceutical gas is still delivered tothe patient over the plurality of breaths, basically the CPU 40 cancarry out the same determination of flows and the like as explained withrespect to the FIG. 3 embodiment. The main difference between this FIG.4 embodiment, and that shown in FIG. 3 is that the patient triggersensor 66 is designed to operate in a way that works with a ventilator46.

For instance, when the ventilator 46 provides gas flow to a patientduring inspiration, it causes a positive pressure in the breathingcircuit. The positive pressure is conducted through the outlet conduit70 and is detected by the patient trigger sensor 66 and is recognized asthe start of inspiration. This is the opposite to the embodiment of FIG.3 where the patient breathes spontaneously and a negative pressure isgenerated during inspiration in the patient device 18; this negativepressure is conducted to the patient trigger sensor 38 of FIG. 3 and isrecognized as the start of inspiration. As can be appreciated, thepatient trigger sensor 38 of FIG. 3 and the patient trigger sensor ofFIG. 4 could be the same pressure sensor and the gas delivery system 44can be set for work with a ventilator or a spontaneously breathingpatient.

Those skilled in the art will readily recognize numerous adaptations andmodifications which can be made to the pharmaceutical gas deliverysystem and method of delivering a pharmaceutical gas of the presentinvention which will result in an improved method and system forintroducing a known desired quantity of a pharmaceutical gas into apatient, yet all of which will fall within the scope and spirit of thepresent invention as defined in the following claims. Accordingly, theinvention is to be limited only by the following claims and theirequivalents.

What is claimed is:
 1. A nitric oxide delivery system comprising: aninlet to connect to a source of pharmaceutical gas comprising nitricoxide; an outlet to connect to a device that introduces thepharmaceutical gas to a patient; a low flow valve in fluid communicationwith the inlet and outlet, wherein the low flow valve delivers thepharmaceutical gas at a first flow rate; a high flow valve in fluidcommunication with the inlet and outlet and in parallel to the low flowvalve, wherein the high flow valve delivers the pharmaceutical gas at asecond flow rate that is higher than the first flow rate; and a gascontrol system that delivers a pulse of the pharmaceutical gas throughone or more of the low flow valve and the high flow valve wherein thecontrol system delivers the pulse of pharmaceutical gas during the firsthalf of the patient's inspiratory cycle.
 2. The system of claim 1,wherein the low flow valve provides a flow of pharmaceutical gas ofabout 1 L/min.
 3. The system of claim 1, wherein the high flow valveprovides a flow of pharmaceutical gas of about 6 L/min.
 4. The system ofclaim 1, wherein the ratio of the flow rate of the high flow valve tothe flow rate of the low flow valve is about 6:1.
 5. The system of claim1, wherein the device that introduces the pharmaceutical gas to thepatient is in fluid communication with a ventilator.
 6. The system ofclaim 1, wherein the device that introduces the pharmaceutical gas tothe patient comprises one or more of a nasal cannula, an endotrachealtube and a face mask.
 7. The system of claim 1, wherein the source ofpharmaceutical gas comprises nitric oxide in a known concentration in acarrier gas.
 8. The system of claim 7, wherein the gas control systemcontrols the volume of pharmaceutical gas delivered during the patient'sbreath based upon the concentration of the nitric oxide in the carriergas.
 9. The system of claim 1, further comprising a patient triggersensor that senses the beginning of a patient's inspiratory cycle.
 10. Amethod of administering a pharmaceutical gas comprising nitric oxide toa patient, the method comprising: providing a nitric oxide deliverysystem having a low flow valve and a high flow valve in parallel flowpaths, wherein the high flow valve delivers the pharmaceutical gas at aflow rate higher than a flow rate of the low flow valve; sensing thebeginning of patient inspiration; and delivering a pulse ofpharmaceutical gas comprising nitric oxide to the patient duringinspiration through one or more of the low flow valve and the high flowvalve.
 11. The method of claim 10, wherein the pulse of pharmaceuticalgas is delivered during the first half of the patient's inspiratorycycle.
 12. The method of claim 10, wherein the low flow valve provides aflow of pharmaceutical gas of about 1 L/min.
 13. The method of claim 10,wherein the high flow valve provides a flow of pharmaceutical gas ofabout 6 L/min.
 14. The method of claim 10, wherein the ratio of the flowrate of the high flow valve to the flow rate of the low flow valve isabout 6:1.
 15. The method of claim 10, wherein the pharmaceutical gascomprises nitric oxide in a known concentration in a carrier gas. 16.The method of claim 15, wherein the volume of pharmaceutical gasdelivered during the patient's breath is based upon the concentration ofthe nitric oxide in the carrier gas.
 17. The method of claim 10, furthercomprising determining the patient's respiratory rate.